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Retinoids and Drugs of Abuse: Implications for Neurological Disease Risk in HIV-1 Infection
 
 
  Clinical Infectious Diseases December 2003;37:S427-S432
 
W. Royal III,1 D. Vlahov,2,4 C. Lyles,4 and C. D. Gajewski3
 
1Morehouse School of Medicine, Atlanta, Georgia; 2New York Academy of Medicine and 3Weil Medical College of Cornell University, New York, New York; and 4Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

 
ABSTRACT
 
Among injection drug users, human immunodeficiency virus (HIV) type 1 infection may be associated with an increased risk of nervous system disease. For HIV-infected drug users with vitamin A deficiency, the overall risk of HIV-related morbidity and mortality may also be higher.
 
In previous studies, levels of retinol, retinol-binding protein, and transthyretin in samples from such individuals were examined and found to be lower than such levels in seronegative control subjects. Also, in studies using an activated mononuclear cell line, all-trans retinoic acid and 9-cis retinoic acid suppressed production of the tumor necrosis factor (TNF)-a and interferon (IFN)-g.
 
However, simultaneous exposure of the cells to morphine at a concentration similar to that to which drug users are exposed resulted in increased production of these cytokines. Therefore, morphine may alter the immunomodulatory effects of retinoids, thereby potentially affecting the clinical outcome of studies involving retinoid administration to HIV-infected drug users and increasing the risk for the development of HIV-related complications, including neurological disease.
 
BACKGROUND
 
Neurological disease occurs in a large percentage of persons with HIV-1 infection and can affect all levels of the nervous system. In general, abnormalities that are directly related to infection with HIV occur late in the course of infection after the onset of significant immunosuppression. These abnormalities, which can involve any area of the nervous system, include peripheral neuropathy, myelopathy, and HIV dementia. In patients with dementia, pathological studies have revealed the presence of characteristic abnormalities, such as disruption of the blood-brain barrier, diffuse white matter pallor, microglial nodules, and multinuclear giant cells with astrocyte proliferation and neuronal loss. The cause of the actual damage to nervous system tissue appears to be related to the effects of neurotoxic compounds released by activated macrophage/microglial cells, astrocytes, and endothelial cells and to toxicity associated with HIV proteins, such as gp120, tat, and nef. Among the inflammatory mediators and products that have been associated with HIV-related neurotoxicity are the proinflammatory cytokines IFN-g, TNF-a, IL-1b, and IL-6, quinolinic acid, nitric oxide, platelet-derived growth factor, and prostaglandins. In addition, there is also increased production and release of proinflammatory chemokines, including macrophage inflammatory protein (MIP)-1a, MIP-1b, RANTES (regulated on activation, normal T cellexpressed and secreted), and monocyte chemoattractant protein (MCP)-1, which can further promote the infiltration of mononuclear phagocytes into nervous system tissue.
 
Micronutrient deficiencies occur commonly in persons with HIV-1 infection. During the course of infection, retinol (vitamin A alcohol) deficiency can occur early on in the setting of significant immunosuppression and AIDS. In seronegative persons, retinol deficiency can be associated with decreased CD4+ lymphocyte numbers and CD4+/CD8+ lymphocyte ratios, and in some persons, these measurements can be increased following administration of retinol. In drug users, low serum vitamin A (retinol) levels have been associated with an increased risk of progression to AIDS and a higher HIV-related mortality. Therefore, in such persons, retinal deficiency can have detrimental effects on the clinical course of HIV-1 infection.
 
Drug use as a risk factor of HIV infection has been apparent since the early days of the epidemic. Currently, drug use remains a leading cause of infection and accounts for a disproportionately high percentage of AIDS cases overall. However, the role of abused substances on the clinical course of HIV infection has been unclear. With respect to opioids, in vitro studies demonstrate that receptor agonists can suppress lymphocyte and monocyte immune function and can increase HIV replication in infected monocytes and macrophages. In vivo, neuropathological studies involving patients with AIDS have revealed evidence of HIV encephalitis more frequently in brains from opioid users than in brains from gay males, suggesting that drug users may be at greater risk for developing HIV dementia. This is in contrast to epidemiological studies that showed no increase in progression of HIV-related nervous system disease among drug users compared with HIV-infected gay men. These persons, however, were at earlier stages of HIV infection, which resulted in a low frequency of infection among both risk groups.
 
In this report are presented studies in which we measured parameters of retinoid metabolism (retinol, retinol-binding protein, and transthyretin) in a cohort of HIV-infected drug users and examined possible effects of morphine on production of proinflammatory cytokines by retinoid-exposed U937 cells, a human mononuclear cell line.
 
DISCUSSION
 
Vitamin A deficiency has been associated with a number of immune effects, such as altered mononuclear cell proliferation and responsiveness associated with either suppressed or enhanced specific cytokine production. Clinically, severe deficiency may be complicated by the occurrence of infectious disorders, as demonstrated by an increased frequency of infectious diarrheal and pulmonary disease in children with vitamin A deficiency and ocular disease. We have reported that levels of retinol are also low in CSF from HIV-seropositive patients with evidence of severe immunosuppression, which may potentially increase the risk for the development of neurological disease in infected persons.
 
Among the potential causes of decreased blood retinol levels are decreased dietary intake and poor intestinal absorption. Indeed, the members of the cohort studied have been found to pursue diets containing less than the recommended content of vitamin A. However, the subjects examined in this study also underwent dietary counseling, and it is, therefore, likely that their dietary vitamin A content exceeded that generally expected of community-based drug users. Among HIV-infected persons, there may be increased vitamin A utilization. This can occur in association with increased hepatic synthesis of acute-phase proteins and because of increased consumption of retinol by immune cells as the immune system mounts specific and nonspecific responses. This increased metabolic demand may not be met with routine vitamin supplementation. RBP and TTR are synthesized by the liver and by the choroid plexus in the CNS. Decreased blood levels of these proteins may occur in the context of impaired liver function. However, even under normal circumstances, RBP that is not bound to retinol is readily excreted by glomerular filtration, with excretion increased in persons with sepsis and decreased in the setting of acute and chronic renal failure. In HIV infection, fever, infection, and other hypermetabolic states result in increased urinary blood flow, which results in increased excretion of RBP and urinary loss of plasma retinol.
 
Therefore, it is possible that a cycle develops in which HIV infection triggers events that result in depressed plasma vitamin A levels, which, in turn, lead to worsening of HIV disease. The effects of changes in retinol, RBP, and TTR levels in blood on the corresponding measurements in CSF are unclear at this time.
 
With respect to opioids, in vitro studies demonstrate that receptor agonists can suppress lymphocyte and monocyte immune function and can increase HIV replication in infected monocytes and macrophages. In addition, as stated previously, HIV encephalitis, which is a complication of late-stage HIV disease, may be identified more frequently in brains from HIV opioid users with AIDS than in brains from their gay male counterparts, suggesting that opioids might increase the rate of HIV disease progression.
 
Epidemiological data from numerous studies, however, have not entirely supported this hypothesis, showing no increase in progression of HIV disease among drug users. For example, in comparisons of HIV seroconverters in the ALIVE study with seroconverters in an Italian drug user cohort, there was no effect of race, heroin use only versus polydrug use, or risk group (comparisons were made with gay men and persons who acquired HIV infection through heterosexual exposure). Notably, Galai et al. demonstrated that during the first 2 years following seroconversion, gay men had more significant declines in CD4+ cell counts than do drug users. In addition, other investigations involving the ALIVE cohort have demonstrated no overall effect of drug use on the median duration of HIV infection before the onset of AIDS or on progression of HIV infection as measured by disease markers such as CD4, neopterin, 2-microglobulin, and total serum IgA levels. Reported drug use patterns, including episodes of withdrawal or overdose, similarly do not appear to alter the course of HIV infection. This finding contrasts with information from animal studies, in which a chronic stable dose of opioid appears to protect from progressive retroviral disease, and intermittent opioid dosing, representing acute episodes of opioid withdrawal, was associated with the development of disease progression in the animals.
 
Neurological complications of HIV infection appear to be linked to mechanisms that involve up-regulation of proinflammatory immune responses. Retinoid compounds can suppress proinflammatory cytokine and chemokine production, effects that may be beneficial to persons with CNS inflammation secondary to HIV infection. In vitro studies of the effects of retinoids on immune function have generally involved incubation of the cell cultures with the retinoid prior to activation. In our studies, morphine, all-trans retinoic acid, 9-cis retinoic acid, and PHA were added simultaneously to the cultures, which might simulate responses obtained with initiation of vitamin A treatment in HIV-infected persons. These studies need to be followed up with investigations of effects of these agents at varying time points, concentrations, and durations of exposure, as well as their effects on differentiated cells and with studies done in vivo. Certainly, experimental effects observed in isolated in vitro systems cannot be expected to precisely model the numerous factors that affect results obtained from epidemiological studies. Nevertheless, such information could prove to be useful in elucidating specific effects of drugs of abuse on retinoid-induced immunomodulation and the potential utility of retinoid compounds in the treatment of neurological disease related to HIV infection.
 
 
 
 
 
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